Sulfa derivatives of 2-amino-5-alkenyl-1, 3, 4-thiadiazoles



Patented June 13, 1950 PATENT OFFICE l I 2 .5i1,s71 SULFA DERIVATIVES Ee2-AMINO-5-ia:

I ALKENYL-IBA-THIADIAZOLES.:- Lucas P. Kyrides and rel-amend ng 'ziemy; st-- Louis; Mmyand Robert W. Stephenson: Seattle.

Wasm; assignors-jso Monsanto Chemical- Com pany,-St. Louis, Mo., a corporation-ofzDelawarer No Drawing} Original application March 12,:1945;

Serial- No 582,411} Divided.,and,thisjjapp1ica= tion August: 8, 11946 Serial-No. 689304 ejClaimsi. (01. zed-239.6)

This invention relates to substituted thiad-ia zoles and more particularly'gtoacertain 2-amino- 5-alkeny1 thiadiazoles and their corresponding 2-acetyl-sulfanilyl and Z-suIfanil-yI derivatives.

vThecompounds of :the. present invention have the following structuralformula- 4 i in which the alkenyl v.residu'e-ihas from 2 to. 4 carbon atoms in its structure. The il amino 5-alkenyl-1,3,4-thiadiazo1esembraced within the scope of the present. invention may be found useful for their propeities. as analgesics and are also useful in thepreparation of other types of thera- [peutic or; pharmaceutical agents The. acetyl sulfanilyl and the sulfanilyl derivatives of. the 2-I amino-'5 alkenyl-1,3,4-thiadiazo1esl of .the...pres 1 ent-invention possess markedactivity in .thecontrolofbacterial growth. The-salts. oi the. re.

spective compounds employed within the scope of the present invention re also contemplated as being within the scope of thisinvention...

The following -5,-alkenyl derivativesgof 2-1 amino-1,3,4l-thiad-iazole are illustrative. of novelcompounds of s the present. m enucnz;

vinyl; allylpropenyl isopropenyl, 1','2-.butenyl,. 2,3-butenyl, 3,4-butenyl, isoloutenyl, secondary.

butenyl and tertiary butenyl.

The 2-amino-5-a1kenyl l,3,4ethiadiazoles.. the present invention may be prepared by any desired procedure. 0ne procedure found useful is that which involves condensation of the appropriate alkenoyl chloride with thiosemiczvbazide, the solution of the resulting reaction product'in water and the subsequent recovery of the product from alkaline solution; An..al-,

ternative procedure is-that which involvesthe condensation of the appropriate -chloralkanoyl. chloride with thiosemicarbazide,-the splittingnfiof HCl bymeans-of hydrolyzing agents, such-as. caustic soda, from the resulting reaction product and the subsequent recovery of the desired-prode not from alkaline solution. The acetylsulfanilyl derivatives of the substituted thiadiazoles of thepresent invention maybe prepared by .reacting N-acetylsulfanilyl chloride with-the appropriate Z-amino-B-alkenyl-1,3,4-thiadiazole. Other acyl residues may be present on the sulfanilyl residue in place ofthe acetyl residue, forv example, formyl, propionyl or butyryl residues. The sulfanilyl derivative may be prepared therefrom by hydrolysis of the appropriate acyl derivative in alkaline solution. The sulfanilyl derivative may beiipr'ep-ared .ialso y reduction'iofthe 2 '(p'fi nitroberizenesulfonyl -5 alkenylf- 1,3,4...-'- thia;

diazole'sio The lattertcompounds may be" pre paredq by reaction of p-anitrobenzenesulfonyli chloride withthei appropriate 2.-'am'ino.-5-'

alkeny1-1,3,4-tl'1iadiazole. I

The following exampleswillserve to illustrate suitable procedures for preparing the novel compoundsrwof' the present {invention These exe amples are not to;. be;-construed.jas limiting the scope. of. the. invention.

Thirtyeseven grams; (G354 mole) of crotonyli chloride. wasicooledj by'lmeansofan ice bathtand 32;2.grams.(0';354 mole): of :thiosemicarbazide;was; added; The: mixture -was agitated for. 8;;hours and cooled durin gxthat. .periodzbyiimeans of an ice bath. Thereaiftersthe 1 ice. bath was replaced r by. ila water bath and. nthe agitationwas con tinned: After nine hours of agitation the ture'qbecame solid: The' 'solid' materialaiwas dis "1' solved in 200 cc. of Water andthBSSDilltiOH WaS filtered. The filtrate was rendered alkaline with 20% caustic soda solution and the solid product was filterediioff uwashediand drie'd.-- Melting point l-l75 C. Weight,:-1l.3 grams (22.6%).

EXAMPLE II Arsolutionrs.or -'11 :grams; (0.078": mole) of; 2-

amino-:S-propenylel,3,4-thiadiazo1e: in cc. of

pyridine/was: prepared.-' To this: solution. 1 was addedfslowly with agitation zl grams'of N- was cornpn'). An additionaliZB- grams of the prod-" uctwasrecovered from'themother liquor by 'concentrationr I EXAMPLE iII 2 sulfanilamido-5-propenyZ+1,BA-thiadiazole Asolution of 17.5 grams-(0'.05l8ino1e) of 2 (N acetylsulfanilamido) 5 propenyl 1,3,4

thiadi'azole in cc. of water'- containin 5.2 gramsof sodium hydroxide was refluxed for 3 hour'sjz Thereafterthe solution was cooledand 3 rendered acidic with glacial acetic acid. The product which separated was filtered off, washed with water and dried. Weight 4.5 grams (29%) Melting point 177-178 C. (decompn).

EXAMPLE IV 2-amz'no-5- (1 -isobutengl) -1,3,4-thiadiazole A mixture of 24 grams (0.202 mole) of isopentenoyl chloride (senecioyl chloride) and 18.5

1 and dried.

grams (0.202 mole) of thiosemicarbazide was pre-;

pared, cooled by means of an ice bath to a tem-' perature below 10 C. and stirred for 8 hours.

After this period, the mixture became solid. The

ice bath was replaced with a cold water bath I and the mixture was thereupon permitted to' come to room temperature (approx. C.). The mixture was allowed to stand for 9 hours and was thereafter dissolved in 200 cc. of water. The

EXAMPLE V 2- (N -acetylsulfanilamido) -5- (1 -isobutenyl) 1,3,4-thiadzazole A solution of 15.5 grams (0.1 mole) of 2-amino- 5(1'-isobutenyl) -1,3,4-thiadiazole in 140 cc. of dry pyridine was prepared. The temperature of the solution was regulated to a point below C. To the solution was added slowly with agitation 27 grams of N-acetylsulfanilyl chloride. The mixture was agitated overnight and thereafter was heated at 60 C. for one hour. Thereupon 140 cc. of water was added and 160 cc. of the resulting mixture was distilled 01f. The desired product crystalized out in the still residue upon cooling and was thereafter filtered off and dried at 8090 C. Weight, 30.6 grams (87.4%). Melting point 240 C.

EXAMPLE V'I Z-sulfanilamido-fi- (1 '-isobutenyl) 4,3,4-

thiadz'azole Five grams (0.0142 mole) of 2-(N -acetylsulfanilamido) -5-(1'isobutenyl) -1,3,4-thiadia zole was dissolved in a solution of 1.5 grams of sodium hydroxide in 37.5 cc. of water at the .boiling point of the solution and the resulting mixture was refluxed for 3 hours. The mixture was thereupon cooled and acidified with glacial acetic acid. The product was filtered off and dried at 70-450 C. overnight. Weight, 4.2 grams. Melting point approx. 235 C.

EXAMPLE VII 2-amino-5-allyl-1,3,4-thiadiaz0le pyl)-1,3,4-thiadiazole, was placed in 400 cc. of 50% alcohol containing 50 grams of sodium hydroxide. Thereafter the mixture was refluxed for-3 hours,'diluted with water andthe alcohol was distilled off. After cooling, the solid product, 2-amino-5-ally1-1,3,4-thiadiazole, was filtered off EXAMPLE VIII 2-(N -acetylsulfanilamidol -5-aZZyZ-1,3,4-

thiadiazole N A-solution-of 14 grams (0.1 mole) of Z-amino- 5-a1lyl-1,3,4-thiadiazole in 130 cc. of dry pyridine was prepared. To this solution was added slowly with agitation, 18.2 grams of N-acetylsulfanilyl i chloride. The mixture was stirred at room temr perature overnight and subsequently was heated to C. for one hour. Thereafter 110 cc. of

water was added and the product which precipitated was filtered off, washed with water and dried.

EXANLPLE IX 2suZfanilamido-5-aZlyZ-1,3,4-thiqdiazole A solution of 13.3 grams (0.05 mole) of 2-(N acetylsulfanilamido) -5-al1yl 1,3,4-thiadiaz0le in 150 cc. of water containing 5.2 grams of sodium hydroxide was refluxed for 3 hours. Thereafter .the solution was cooled and rendered acidic with ofi. The wet cake. 2-amino-5-(3-chloroproglacial acetic acid. The product which separated was filtered off, washed with water and dried.

EXAMPLE X 2-amino-5-vinyZ-1,3,4-thiadiazole A mixture of 56 grams (0.5 mole) of betachloropropionyl chloride and 39 grams (0.5 mole) of thiosemicarbazide was prepared and agitated for 2 hours at a temperature below 10 C. Thereafter the temperature-of the mixture was allowed to rise to room temperature (approx. 25 0.). After several hours of agitation, the reaction mixture was dissolved in approx; 400 cc. of warm 50% alcohol containing 50 grams of sodium hydroxide. Thereafter the mixture was refluxed for 3 hours, water was added, the alcohol was distilled off, and the mixture was cooled. The solid product, 2-amino-5-vinyl-1,3,4-thiadiazole, was filtered off, washed and dried. In place of beta-chloropropionyl chloride, alpha-chloroprorpionyl chloride may be employed.

EXAMPLE XI 2- (N -acetylsulfanilamz'do) -5-vznyl-1,3,4-

thiadiazole A solution of 12.7 grams (0.1 mole) of Z-amino- 5-vinyl-1,3,4-thiadiazole in 150 cc. of dry pyridine was prepared. The temperature of the solution was regulated to a point below 30 C. To the solution was added slowly with agitation 78.2 grams of N-acetylsulfanilyl chloride. The mixture was agitated overnight and thereafter was heated at '50-60 C. for one hour. Thereupon cc. of water was added and cc. of the resulting mixture was distilled off. The desired product crystallized out in the still residue upon cooling and was thereafter filtered off and dried.

EXAMPLE XII 2-suZfaniZamido-5-2JinyZ-1,3,4-thiadiazole Ninety-nine grams (0.05 mole) of 2-(N -acetylsulfanilarnido) -5-vinyl-1,3,4-thiadiazole was dissolved in a solution of. 3 grams sodium hydroxide in'80 cc. of water at the boiling point of the solution and the resulting mixture was refluxed for 3 hours. The mixture was thereupon cooled and acidified with glacial acetic acid. The product was filtered ofi, washed with water and dried at NJ-80 C. overnight.

EXAMPLE XIII Z-amino-5-isopropenyl-1,3,4-thiadiazole A mixture of 37 grams (0.354 mole) of methacroylchloride and 32.2 grams (0.354 mole) of thiosemicarbazide was prepared. The mixture was agitated for 8 hours and cooled during that period by means of an ice bath. Thereafter the ice bath was replaced by a water bath and the agitation was continued until the mixture became solid. The solid material was dissolved in 200 cc. of water and the solution was filtered. The filtrate was rendered alkaline with 20% caustic soda solution and the solid product was filtered off, washed and dried.

As an alternative procedure, a mixture of '71 grams (0.5 mole) of beta-chloroisobutyryl chloride and 39 grams (0.5 mole) of thiosemicarbazide was prepared and agitated for 2 hours at a temperature below 10 C. Thereafter the temperature was allowed to rise to room temperature (approx. 25 0.). After several hours of agitation, the reaction mixture was dissolved in approx. 400 cc. of warm 50% alcohol containing 50 grams of sodium hydroxide. Thereafter the mixture was refluxed for 3 hours, water Was added, the alcohol was distilled off and the mixture was cooled. The solid product was filtered ofi, washed and dried.

EXAMPLE XIV 2-(N -acetylsuljanilamido) 5-isppropenyl-L3A- thz'adiazole This compound was prepared according to the procedure described in Example 2, substituting 11 grams of 2-amino-5-isopropenyl-1,3,4-thiadiazole for the 2-amino-5-propenyl-1,3,4-thiadiazole employed in that procedure.

EXAMPLE XV 2-sulfcmilamido-5-is1opropenyl-1 ,3,4-thz'adz'az0le This compound was prepared according to the procedure described in Example 3, substituting 17.5 grams of 2-(N -acetylsulfanilamido) -5-isopropenyl-1,3,4-thiadiazole for the 2-(N -acetylsulf-anilamido) -5-propenyl-1,3,4-thiadiazole employed in that procedure.

The 2-amino-5-alkenyl-1,3,4-thiadiazoles of the present invention may also be employed in the form of the acid salt derivatives, such as the hydrochloride, sulfate, benzoate or acetate. These salt derivatives may be prepared by reacting in equimolecular proportions the 2-amino-5-alkenyl-1,3,4-thiadiazole with the appropriate acid in aqueous or organic solvent solution, according to the procedure known in this art for the preparation of acid salt derivatives of basic organic nitrogen compounds.

This application is a division of our co-pendin application, Serial Number 582,411, filed March 12, 1945, now Patent No. 2,420,434.

While the compositions of the present invention have been described and illustrated in the foregoing specification and examples, it is to be observed that the present invention is not to be construed as being limited in respect to any particular substances, proportions, conditions or combinations except as defined in the claims.

We claim:

1. A compound from the group consisting of those having the following formula:

R-Osomn-c'i t i-Aiken i REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,358,031 Roblin et a1 Sept. 12, 1944 FOREIGN PATENTS Number Country Date 61,112 Denmark July 12, 1943 

1. A COMPOUND FROM THE GROUP CONSISTING OF THOSE HAVING THE FOLLOWING FORMULA: 